Jack C. Wright

The role of situational demands and cognitive competencies in behavior organization and personality coherence.

Consistency in the natural organization of aggressive and prosocial (constructive) behavior, assessed repeatedly in vivo over a summer in a residential camp for children, was predicted from situational and personal characteristics. Similarity of situations in the types of competencies they demand in part predicted cross-situational consistency in individual differences in aggressive behaviors (Study 1). Study 2 examined the effect of cognitive competence on the discriminative patterning of behavior variation across situations. More cognitively competent Ss showed such discriminative patterning, which was reflected in greater Person X Situation interaction variance in their prosocial behavior.

Conditional hedges and the intuitive psychology of traits.

The view that the intuitive psychologist exaggerates the consistency of personality implies that dispositional constructs are condition-free summary statements about generalized behavioral tendencies. This article considers the alternative view that dispositional constructs summarize specific condition-behavior contingencies. Despite their condition-free appearance, the dispositional constructs used by child and adult observers in their personality descriptions were hedged by modifiers that reflected knowledge of the variability of behavior. Childrens descriptions of their aggressive and withdrawn peers included probabilistic hedges that indicated uncertainty about the occurrence of behaviors (person sometimes does x). Adults made dispositional attributions with greater certainty, but more often modified them with conditional statements which identified when dispositionally relevant behaviors might be observed (person does x when y). Content analyses of these conditional statements revealed that adults systematically linked specific categories of conditions (e.g., aversive interpersonal events) to specific categories of social behavior (e.g., aggressive acts). The results help to clarify how people may hedge dispositional terms in ways that reflect their sensitivity to covariation between situations and behaviors.

Probing the Depths of Informant Discrepancies: Contextual Influences on Divergence and Convergence

This study examined how a contextual approach to child assessment can clarify the meaning of informant discrepancies by focusing on childrens social experiences and their if…then reactions to them. In a sample of 123 children (M age = 13.30) referred to a summer program for children with behavior problems, parent–teacher agreement for syndromal measures of aggression and withdrawal was modest. Agreement remained low when informants assessed childrens reactions to specific peer and adult events. The similarity of these events increased consistency within informants but had no effect on agreement between parents and teachers. In contrast, similarity in the pattern of social events children encountered at home and school predicted informant agreement for syndromal aggression and for aggression to aversive events. Our results underscore the robustness of informant discrepancies and illustrate how they can be studied as part of the larger mosaic of person–environment interactions.

Gender similarities and differences in Children's social behavior : Finding personality in contextualized patterns of adaptation

This research examined how a contextualist approach to personality can reveal social interactional patterns that are obscured by gender comparisons of overall behavior rates. For some behaviors (verbal aggression), girls and boys differed both in their responses to social events and in how often they encountered them, yet they did not differ in overall behavior rates. For other behaviors (prosocial), gender differences in overall rates were observed, yet girls and boys differed more in their social environments than in their responses to events. The results question the assumption that meaningful personality differences must be manifested in overall act trends and illustrate how gender differences in personality can be conceptualized as patterns of social adaptation that are complex and context specific.

A phase II trial of the Src-kinase inhibitor saracatinib after four cycles of chemotherapy for patients with extensive stage small cell lung cancer: NCCTG trial N-0621.

INTRODUCTION To assess the efficacy and the Src-kinase inhibitor saracatinib (AZD-0530) after four cycles of platinum-based chemotherapy for extensive stage small cell lung cancer (SCLC). METHODS Patients with at least stable disease received saracatinib at a dose of 175 mg/day by mouth until disease progression, unacceptable toxicity, or patient refusal. The primary endpoint was the 12-week progression-free survival (PFS) rate from initiation of saracatinib treatment. Planned interim analysis in first 20 patients, where 13 or more patients alive and progression-free at 12-weeks would allow continued enrollment to 40 total patients. RESULTS All 23 evaluable patients received platinum based standard chemotherapy. Median age was 58 years (range: 48-82). 96% of patients had a performance status of 0/1. Median of two cycles given (range: 1-34). All 23 (100%) patients have ended treatment, most for disease progression (19/23). The 12-week PFS rate was 26% (6/23; 95% CI: 10-48%). From start of standard chemotherapy, median PFS was 4.7 months (95% CI: 4.5-5.1) and median OS was 11.2 months (95% CI: 9.9-13.8). Eight (35%) and three (13%) patients experienced at least one grade 3/4 or grade 4 AE, respectively. Commonly occurring grade 3/4 adverse events were thrombocytopenia (13%), fatigue (9%), nausea (9%), and vomiting (9%). CONCLUSIONS Saracatinib at a dose of 175 mg/day by mouth is well tolerated. However, the PFS rate observed at the pre-planned interim analysis did not meet the criteria for additional enrollment.

Biomarker‐driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer

Src tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP‐sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6‐month survival. A Simon MinMax two‐stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28‐day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6‐month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker‐driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin‐like growth factor‐binding protein 2 [IGFBP2] “top scoring pairs” polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker‐positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3′ untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6‐month survival endpoint. As the frequency of biomarker‐positive patients was very low (<3%), the study was closed. Although we were unable to conclude whether enriching for a subset of second/third line pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6‐month survival, we demonstrate that testing pancreatic tumor samples for a biomarker‐driven, multicenter study in metastatic pancreas cancer is feasible.

Peer-Nominated Deviant Talk Within Residential Treatment: Individual and Group Influences on Treatment Response

This research examined deviant talk during summer residential treatment using peer nominations and extensive field observations. Participants were 239 youth (Mage = 12.62, SD = 2.60; 67% male), nested in 26 treatment groups. Deviant talk was present in this setting, showed individual differences, and increased over time, especially for younger boys. As expected, its relationship to treatment response was moderated by peer behavior. Initial levels of individual deviant talk were related to clinical improvement, but primarily when peer deviant talk was low. Initial levels of peer deviant talk were related to higher than expected end of treatment aggression, especially for youth who were high in deviant talk. Deviant talk effects were observed for staff impressions of change and observations of aggression and adjustment. Initial antisocial behavior affected whether individual or peer levels of deviant talk more heavily influenced treatment response. Implications for clinical assessment and treatment monitoring are discussed.

Abstract 35: Phase I study of dasatinib in combination with bevacizumab in advanced solid tumors (NCT01445509).

Background: Inhibition of the MAPK pathway with sorafenib and neutralization of VEGF with bevacizumab (B) resulted in clinical benefit with interactive toxicity. Dasatinib (D) is a broad spectrum tyrosine kinase inhibitor with high affinity for SRC family kinases. We hypothesized that using this upstream inhibitor of the MAPK pathway with B would maintain activity with less interactive toxicity. Methods: A 3+3 dose escalation design incorporated with B 5mg/kg q2wk plus daily D 50, 70 and 100 mg in dose levels [DL] 1/2/3, then B 10mg/kg q 2wk plus D 100mg in DL4. DLT was defined during the first 6 weeks of treatment. Safety was assessed each 28d cycle and disease was reassessed every 2 cycles. Results: 19 pts were treated in the dose escalation portion on 4 DLs. Pts (17F/2M) had a median age of 64 yrs (25-79), ECOG PS 0-1, and normal end-organ function. Most (14/19) pts had metastatic gynecologic cancers (6 endometrial/5 ovarian-peritoneal/2 cervix/1 rectovaginal GIST). Other cancers included breast (2), pancreatic neuroendocrine (1), medullary thyroid (1) and melanoma (1). Median number of prior treatments was 4 (1-11). The highest planned dose combination was examined without exceeding the MTD. No DLT was observed. Grade (g) 3 events included hypertension (2), pleural effusion (2), dyspnea (1) and pulmonary hypertension (1). D-mediated marrow suppression was observed in 12 pts: anemia (g1/2 [12 pts]), lymphopenia (g1/2 [9pts]; g3 [1pt]), thrombocytopenia (g1/2 [5pts]), and neutropenia (g1/2 [4pts]). Confirmed PR was seen in 1/17 evaluable pts, a pt with HER2+ breast cancer (5 mo). Stabilization >/= 4 mo occurred in 9 pts (median 9 mo [4-18+mo]), yielding clinical benefit in 59%. Conclusions: D 100 mg daily with B 10mg/kg q2wk appears to be active and is well-tolerated in pts with advanced solid tumors. G 3 adverse events were uncommon and g 4 events or severe marrow toxicities were not observed at the doses planned and examined. An expansion cohort is now accruing with functional imaging, tumor biopsies, and blood sampling for measurement of biochemical changes in SRC and VEGF signaling pathways. Citation Format: Jung-Min Lee, Christina Annunziata, Anne M. Noonan, John L. Hays, Lori Minasian, Jo Anne Zujewski, Helen Chen, John Wright, Nicole Houston, Elise C. Kohn. Phase I study of dasatinib in combination with bevacizumab in advanced solid tumors (NCT01445509). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 35. doi:10.1158/1538-7445.AM2013-35

Abstract 4712: Evidence of clinical efficacy of the combination of flavopiridol (Alvocidib) and cisplatin in platin-resistant ovarian and primary peritoneal carcinoma: Phase 2 trial MC0261

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Based upon preclinical synergy and prior phase 1 study results, the clinical efficacy of flavopiridol combined with cisplatin was assessed in patients with recurrent ovarian and primary peritoneal cancers. Methods: A two cohort phase 2 trial of cisplatin (60 mg/m2 IV) followed by flavopiridol (100 mg/m2 IV, 24 h continuous infusion; 21 day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant ovarian/primary peritoneal cancers (defined by disease progression > vs. 2X the post-treatment nadir – was required, as was ECOG performance <2 and exposure to only one prior treatment regimen. Results: Forty-five patients were enrolled between April 20, 2004 and March 4, 2010 – 40 platin-resistant patients (Group 1), and 5 platin-sensitive patients (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12); 39 of the 40 eligible patients have now discontinued treatment. While only 10% of all patients incurred grade 4 toxicities, grade 3 toxicities were seen in the majority (65%). The most frequent grade 3 and 4 toxicities were neutropenia (all grade 3, 17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Sensory neuropathy, grade 1 or 2, was observed in 75% of all patients – with grade 3 and 4 neuropathy not observed primarily due to pre-specified aggressive dose reductions. Six patients (15%) in Group 1 achieved a confirmed response (1 CR, 5 PR), with a median response duration of 119 days (range 84-212). Ten additional Group 1 patients (32.5%) experienced maintained stable disease. Median Group 1 overall time to progression was 3.7 months; overall survival was 17.2 months. Pilot assessment of attained ascites flavopiridol level and sensitivity of patient ascitic tumor cells to flavopiridol confirmed that patient flavopiridol levels were consistent with observed clinical antitumor efficacy. In Group 2, although 2 of 5 patients also responded (40%; 2 PR), the cohort was closed due to poor accrual. Conclusions: The combination of flavopiridol and cisplatin has promising clinical activity in both platin-sensitive and platin-resistant ovarian and primary peritoneal cancers. Supported in part by NCI [CA097129][1], CA15083 and CM62205; clinicaltrials.gov identifier [NCT00083122][2] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4712. doi:10.1158/1538-7445.AM2011-4712 [1]: /lookup/external-ref?link_type=GEN&access_num=CA097129&atom=%2Fcanres%2F71%2F8_Supplement%2F4712.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00083122&atom=%2Fcanres%2F71%2F8_Supplement%2F4712.atom